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ToxSci Advance Access originally published online on May 28, 2008
Toxicological Sciences 2008 106(1):74-82; doi:10.1093/toxsci/kfn104
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Decreased Urinary Beta-Defensin-1 Expression as a Biomarker of Response to Arsenic

Christine M. Hegedus*, Christine F. Skibola*,1, Marcella Warner*, Danica R. Skibola*, David Alexander*, Sophia Lim*, Nygerma L. Dangleben*, Luoping Zhang*, Michael Clark*, Ruth M. Pfeiffer{dagger}, Craig Steinmaus{ddagger}, Allan H. Smith*, Martyn T. Smith* and Lee E. Moore{dagger},1

* School of Public Health, University of California, Berkeley, California 94720-7356 {dagger} Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892-7420 {ddagger} Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California 94612

1 To whom correspondence should be addressed at School of Public Health, Division of Environmental Health Sciences, Room 237A, B84 Hildebrand Hall MC7356, University of California, Berkeley, CA 94720-7356. Fax: (510) 642-0427; (301) 402-1819. E-mails: chrisfs{at}berkeley.edu, moorele{at}mail.nih.gov.

Received February 28, 2008; accepted May 21, 2008


  Abstract

Ingestion of arsenic (As) through contaminated drinking water results in increased risks of skin, lung, kidney, and bladder cancers. Due to its association with kidney and bladder cancers, we hypothesized that analysis of the urinary proteome could provide insight into the mechanisms of As toxicity. Urine from participants in a cross-sectional As biomarker study conducted in Nevada, classified as having either high (≥ 100 µg total urinary As/l) or low exposure (< 100 µg total urinary As/l) was analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Two polypeptides, 2.21 and 4.37 kDa, were significantly decreased in the high exposure group (p < 0.05) and were limited to men when stratified by sex. To replicate these findings, urine from participants in a second As study in Chile was analyzed and results confirmed the decrease of the 4.37 kDa polypeptide as well as a 4.76 kDa polypeptide among highly exposed men. These peaks were identified and confirmed as human β-defensin-1 (HBD-1) peptides. In a separate in vitro experiment, gene expression analysis of As-treated cell lines demonstrated reduced HBD1 mRNA confirming that the observed decrease in HBD-1 resulted from As exposure. HBD-1 is an antimicrobial peptide constitutively expressed in multiple tissues including epithelial cells of the respiratory and urogenital systems. Recent studies support its role as a tumor suppressor gene for urological cancers suggesting that decreased HBD-1 levels may play a role in the development of cancers associated with As exposure. Further studies are warranted to investigate the role of HBD-1 in As-related toxicity.

Key Words: arsenic; human beta-defensin-1; proteomics; SELDI-TOF MS.


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